Field of the Invention
The present invention is directed to pharmaceutical compositions and methods for reducing systemic absorption of therapeutic compounds while enhancing targeting of such compounds or agents to, inter alia, the central nervous system (CNS) via intranasal administration. More specifically, use of vasoconstrictors as a pretreatment or in a pharmaceutical composition with therapeutic(s), delivered intranasally, to increase targeting to, inter alia, the CNS while limiting systemic exposure.
Description of the Related Art
It is known that intranasal administration of therapeutic compounds or agents may, in some cases, increase the effectiveness of certain therapeutic compounds or agents in bypassing the blood brain barrier (BBB) and delivering the compound or agent directly to the CNS. Thus, intranasal administration of therapeutic compounds may allow increased prevention and/or treatment of certain diseases or conditions.
It is also known that greater than 98% of small molecule and nearly 100% of large molecule CNS drugs developed by the pharmaceutical industry do not cross the BBB. Intracerebroventricular or intraparenchymal drug administration can directly deliver therapeutics to the brain; however, these methods are invasive, inconvenient, and impractical for the numbers of individuals requiring therapeutic interventions for treating CNS disorders. Intranasal drug administration is a non-invasive and convenient means to rapidly target therapeutics of varying physical and chemical properties to the CNS. The olfactory and trigeminal neural pathways connecting the nasal passages to the CNS are clearly involved in the delivery of therapeutic compounds applied via intranasal administration to the upper third of the nasal cavity. In addition to these neural pathways, perivascular pathways, and pathways involving the cerebrospinal fluid or nasal lymphatics may play a central role in the distribution of therapeutics from the nasal cavity to the CNS. Numerous therapeutics have been delivered to the CNS following intranasal administration, to both the upper third and lower two-thirds of the nasal cavity, and have demonstrated pharmacological effects in animals and in humans.
The intranasal method of drug delivery holds great promise as an alternative to more invasive routes, however, a number of factors limit the efficiency of intranasal delivery to the CNS. Absorption of intranasally applied drugs into the capillary network in the nasal mucosa can decrease the amount of drug available for direct transport into the CNS. Additional factors within the nasal cavity, including the presence of nasal mucociliary clearance mechanisms, metabolizing enzymes, efflux transporters and nasal congestion can also reduce the efficiency of delivery into the CNS. In particular, therapeutic compounds may be absorbed into the blood and/or delivered to peripheral (non-target) tissues, thus reducing delivery of the compound to the target. As a result, the efficacy of administering therapeutic compounds to the lower two-thirds of the nasal cavity with the goal of delivering therapeutics to the CNS is greatly diminished. Further, the efficacy of administering therapeutic compounds to the upper one-third of the nasal cavity as a means to target therapeutics to the CNS could be improved.
It would be desirable to reduce absorption of intranasally-administered therapeutic compounds or agents into the blood and delivery to non-target or peripheral tissues. It would be further desirable to increase deposition and delivery of the therapeutic compounds or agents to, inter alia, the CNS, e.g., within the olfactory epithelium, the olfactory bulbs as well as the lymphatic system, and it would be desirable to increase therapeutic compound targeting relative to the blood to the frontal cortex, anterior olfactory nucleus, hippocampus, hypothalamus, pons, midbrain, medulla, cerebellum and to the meninges. It would be further desirable to provide an intranasal delivery method and pharmaceutical composition(s) that are effective and efficient in facilitating delivery of therapeutic compounds to the CNS, regardless of whether the therapeutic composition is delivered to the upper one-third or lower two-thirds of the nasal cavity.
The present invention addresses, inter alia, these issues.